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Event Overview

Speaker & Participant Remarks

Dr. Geoff Porter- Monday, April 12th, 2010

The third issue important to this dialogue is "How discovery makes its way into clinical cancer care". I've entitled my introduction to this topic "Thoughtful Process" to reflect the incremental nature and deliberate thought that goes into the true progress that has been made in cancer research.

The pyramid displayed here is intended, at a very simple level, to depict how a new discovery gets into clinical care. Such a new discovery could be anything from a novel finding in the lab, a new technology, new radiation equipment, to something discovered in the clinic quite by happenstance - it does not really matter. Characteristically fundamental "basic science" of the discovery involves in vitro, in vivo and animal models. Potential novel therapies felt to have promise via these approaches enter into the clinical research in patients. Phase 1 studies (largely studies of toxicity and tolerability), phase 2 studies (intended to examine response rates, typically done in patients with quite advanced disease), and phase 3 studies (randomized trial that compares that novel treatment with established standard) is the current logical sequence of clinical trials in cancer. Treatment modalities undergo a very complicated approval process that involves national, provincial and regional processes. This pyramid, although appealing in concept, is in reality much more complex. There are multiple interspersed elements which aren't in this slide and there are multiple loops, both forwards and backwards, which may exist for a given new therapy.

Overall however, this logarithm is purposeful; it gets treatments which are shown to be efficacious into clinical environment. How does this actually happen from a practical perspective? There are many drivers involved, probably the most important being knowledge. The existing knowledge -with regards to the disease and treatment and the new knowledge, comes together to establish the potential impact of the discovery. The degree of burden of the given cancer; its stage, its incidence and its impact are also a clear driver. Most cancer success has occurred, using a baseball metaphor, as a series of incremental singles; a series of singles can score runs. Thankfully there have been several home runs and hopefully there will be more into the future, but we have to remember we can't treat the incremental single disparagingly. Feasibility of research and feasibility of the potential treatment in clinical arena are also important drivers. As we have already heard economics plays a major role, both in the research and in the approval stage. Finally knowledge translation through a variety of mechanisms such as rounds, multi-disciplinary case conferences, published scientific literature, is critical.

There are legitimate criticisms with this present state of affairs:

1. Timing - It can take over a decade to get a legitimate novel discovery into clinical care where it can make a difference for cancer patients.


2. Hype versus hope - Seeing cancer patients in clinical the day after the latest front page Globe and Mail cancer discovery reminds us of this issue. Such a day can be, all at the same time, the most challenging, frustrating and exciting day in clinic that you are going to have for the next few month.


3. Small improvements are the goal - There are many that make the very cogent argument that the bar of cancer efficacy is in fact set too low. They would note that this has encouraged further funding of research looking for smaller and smaller increments of gain. Statistical and clinical significance may not align in this regard.


4. Toxicity should be low - When a treatment that has shown only a modest benefit, or even less, we must set the safety bar perhaps high; this may in fact detrimentally interfere with promising therapies making their way through the aforementioned system.


5. Big "all comer" studies - The standard model of clinical trials is biased towards unselected patients. Randomized Phase 3 trials are often performed with the goal of being generalizable; they take often all comers with a wide variety of heterogeneous patient populations. The downside is at a biologic level the treatment may be only affecting a sub population, which is not identified due to the inclusive trial design


6. Regulatory - The cost of performing cancer research, and thus the cost of the potential product are increasing for many reasons. There is no doubt that increasing regulatory requirements are a major driver in this regard. A recent study showed that greater than 18% of clinical trial costs relate purely to the management of regulatory issues.

In cancer, the issue of efficacy versus effectiveness has become increasingly recognized. Efficacy refers to how well a potential treatment works in the ideal environment (e.g., the lab, the relatively stringent environment of a phase 3 clinical trial). Effectiveness refers to how it works in the real world. Ideally these are similar; practically they are often not.

Effectiveness is now a key part of the American healthcare reform. Now I know that this is an Atlantic conference but I don't think we can ignore what is happening south of the border. Comparative Effectiveness Research (CER) is defined as research that compares different interventions and strategies to prevent, diagnose, treat or monitor cancer. Its purpose is to inform patients, providers and decision-makers, about what interventions are most effective, not necessarily efficacious, but effective for which patients under which circumstances. One can only imagine the impact of good translational research on effectiveness. CER has rapidly become a buzz word just as it was announced about a year ago that $1.1 billion would be allocated to CER through three agencies. It is expected that this will play a major role in the health care reform happening in the US. In Canada, I would submit we do CER, and doit quite well; we just need to do it more.

Our purposeful system has served cancer patients well but it clearly needs to evolve as we go forward in the molecular and genomic era that cancer patients and potential cancer patients live. In my view the Atlantic node of the TFRI is going to be very critical to this evolution.